Design,synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine‐resistant strain

A series of novel bisquinoline compounds comprising N¹‐(7‐chloroquinolin‐4‐yl) ethane‐1,2‐diamine and 7‐chloro‐N‐(2‐(piperazin‐1‐yl)ethyl)quinolin‐4‐amine connected with 7‐chloro‐4‐aminoquinoline containing various amino acids is described. We have bio‐evaluated the compounds against both chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8‐ and 10.6‐fold superior activity as compared to chloroquine (CQ; IC₅₀ = 0.255 ± 0.049 μm ) against the K1 strain with IC₅₀ values 0.137 ± 0.014 and 0.026 ± 0.007 μm , respectively. Furthermore, compound 7 also displayed promising activity against the 3D7 strain (IC₅₀ = 0.024 ± 0.003 μm ) of P. falciparum when compared to CQ. All the compounds in the series displayed resistance factor between 0.57 and 4.71 as against 51 for CQ. These results suggest that bisquinolines can be explored for further development as new antimalarial agents active against chloroquine‐resistant P. falciparum.     

The Role of Magnesium in Post-thyroidectomy Hypocalcemia

Background

The purpose of this study was to determine the prevalence of hypomagnesemia in patients undergoing thyroidectomy and evaluate the relationship of hypomagnesemia with transient and severe hypocalcemia.

Materials and methods

This was a prospective observational study of 50 patients undergoing thyroidectomy. Blood samples were collected pre- and postoperatively for calcium, albumin, magnesium, phosphorous and parathormone (PTH). Signs, symptoms of hypocalcemia and volume of intravenous fluids used perioperatively were documented. The statistical analysis was performed using STATA I/C 10.1.

Results

Preoperatively, twelve patients (24 %) had hypomagnesemia and one (2 %) hypocalcemia. On the first postoperative day, hypomagnesemia was seen in 70 % and hypocalcemia in 30 %. A similar trend was observed in the fall and rise of postoperative calcium and magnesium values (p = 0.41). Severe hypocalcemia was present in three patients (6 %). All three patients had a very low postoperative PTH (<2 pg/ml). Among them, two patients (66 %) had hypomagnesemia and their hypocalcemia responded to intravenous magnesium correction. Significant risk factors for postoperative hypocalcemia include a higher volume of fluid used perioperatively and low postoperative PTH (<8 pg/ml) (p = 0.01 and 0.03, respectively).

Conclusion

Preoperative hypomagnesemia (24 %) was prevalent in this cohort of patients. Postoperative hypomagnesemia is a common event (70 %) following total thyroidectomy, and magnesium levels tend to mimic the calcium levels postoperatively. The cause of hypocalcemia post-thyroidectomy in this study is mainly a factor of parathyroid function and fluid status. Severe hypocalcemia is a rare event, and hypomagnesemia is associated in the majority of these patients. The role of magnesium correction to alleviate severe hypocalcemia needs to be further studied.

     

Vitamin D supplementation for treatment and prevention of pneumonia in under-five children: <Emphasis Type="Italic">A randomized double-blind placebo controlled trial</Emphasis>

Objective

To evaluate the efficacy of single oral mega-dose of Vitamin D3 for treatment and prevention of pneumonia in underfive children.

Design

Randomized, double blind, placebo-controlled trial.

Setting

Tertiary-care hospital.

Participants

324 children (of 980 assessed) between 6 mo-5 y age (median (IQR): 12 (7,19.8) mo) with WHO-defined severe pneumonia. Of these, 126 (39%) were vitamin D deficient (serum 25(OH)D <12 ng/mL).

Intervention

100,000 IU of oral cholecalciferol (n= 162) or placebo (n= 162) in single dose, administered at enrolment.

Outcome variables

Primary: Time to resolution of severe pneumonia and proportion of children having recurrence of pneumonia in next 6 months; Secondary: Change in serum levels of 25(OH)D; immunoglobulins IgA, IgG, IgM, and cathelicidin 2 weeks following supplementation; and time taken for overall resolution of illness.

Results

Median (95% CI) time for resolution of severe pneumonia was 30 (29, 31) h in the vitamin D group as compared to 31 (29,33) h in the placebo group [adjusted hazard ratio (95% CI): 1·39 (1·11, 1·76); P=0·005]. The risk of recurrence of pneumonia in next 6 months was comparable in the two groups [placebo: 36/158 (22·8%); vitamin D: 39/156 (25%); RR (95% CI): 1·13 (0·67,1·90); P=0·69]. Proportion of vitamin D deficient children declined from 38% to 4% in the supplementation group, and from 41% to 33% in the placebo group, two weeks after supplementation. There was no significant effect of vitamin D supplementation on serum levels of cathelicidin, IgA and IgG. The time taken for complete recovery from pneumonia, duration of hospitalization, and fever clearance time were comparable for the two groups. No adverse event was noted related to the intervention.

Conclusion

There is no robust evidence of a definite biological benefit, either for therapy or prevention, to suggest a routine megadose supplement of vitamin D3 for under-five children with severe pneumonia.

     

Lapatinib nano-delivery systems: a promising future for breast cancer treatment

Introduction: Breast cancer stands the second prominent cause of death among women. For its efficient treatment, Lapatinib (LAPA) was developed as a selective tyrosine kinase inhibitor of receptors, overexpressed by breast cancer cells. Various explored delivery strategies for LAPA indicated its controlled release with enhanced aqueous solubility, improved bioavailability, decreased plasma protein binding, reduced dose and toxicity to the other organs with maximized clinical efficacy, compared to its marketed tablet formulation.

Areas covered: This comprehensive review deals with the survey, performed through different electronic databases, regarding various challenges and their solutions attained by fabricating delivery systems like nanoparticles, micelle, nanocapsules, nanochannels, and liposomes. It also covers the synthesis of novel LAPA-conjugates for diagnostic purpose.

Expert opinion: Unfortunately, clinical use of LAPA is restricted because of its extensive albumin binding capacity, poor oral bioavailability, and poor aqueous solubility. LAPA is marketed as the oral tablet only. Therefore, it becomes imperative to formulate alternate efficient multiparticulate or nano-delivery systems for administration through non-oral routes, for active/passive targeting, and to scale-up by pharmaceutical scientists followed by their clinical trials by clinical experts. LAPA combinations with capecitabine and letrozole should also be tried for breast cancer treatment.     

FDC:TFH Interactions within Cervical Lymph Nodes of SIV-Infected Rhesus Macaques

Cerebrospinal fluid (CSF) drains via the lymphatic drainage pathway. This lymphatic pathway connects the central nervous system (CNS) to the cervical lymph node (CLN). As the CSF drains to CLN via the dural and nasal lymphatics, T cells and antigen presenting cells pass along the channels from the subarachnoid space through the cribriform plate. Human immunodeficiency virus (HIV) may also egress from the CNS along this pathway. As a result, HIV egressing from the CNS may accumulate within the CLN. Towards this objective, we analyzed CLNs isolated from rhesus macaques that were chronically-infected with simian immunodeficiency virus (SIV). We detected significant accumulation of SIV within the CLNs. SIV virion trapping was observed on follicular dendritic cells (FDCs) localized within the follicular regions of CLNs. In addition, SIV antigens formed immune complexes when FDCs interacted with B cells within the germinal centers. Subsequent interaction of these B cells with CD4+ T follicular helper cells (T_FHs) resulted in infection of the latter. Of note, 73% to 90% of the T_FHs cells within CLNs were positive for SIV p27 antigen. As such, it appears that not only do the FDCs retain SIV they also transmit them (via B cells) to T_FHs within these CLNs. This interaction results in infection of T_FHs in the CLNs. Based on these observations, we infer that FDCs within the CLNs have a novel role in SIV entrapment with implications for viral trafficking.     

Integrating binocular vision assessment in refractive surgery work-up: Proposition and protocol

Refractive surgeries are one of most commonly performed surgeries for correcting visual impairment due to refractive errors. With the increase in demand for refractive surgeries, there is an enormous strain on the operating surgeon for delivering ideal outcomes i.e 20/20 visual acuity. Regression, under-correction and ectasia are the most dreaded complications post-refractive correction, for the surgeon as well as the patient. They have significant effects on the quantity of the vision and most importantly on the quality of life of the patient. With the advent of digital era and jobs requiring the eyes being glued to the screen for hours there has been a surge in the patients presenting with complaints of asthenopia, glare, halos, and difficulty in focusing; pointing towards diagnosis of non-strabismic binocular vision anomalies (NSBVA). NSBVA in a postrefractive surgery patient may masquerade as regression or under-correction. However, timely diagnosis of NSBVA in such patients would prevent the greater harm caused by wrongful re-correction. Home- and office-based vision therapy results in improvement in visual acuity in a large majority of these patients. This preferred practice pattern intends to guide the refractive surgeons to diagnose and treat the postrefractive surgery NSBVA following a case-based and algorithmic approach. It also emphasizes the inclusion of the binocular vision assessment as a part of the pre-operative workup for patients undergoing refractive procedures.